Females Of Childbearing Potential Research Articles

Prevalence of polypharmacy and factors impacting psychotropic prescribing patterns in women of childbearing potential at inpatient mental health services in Qatar.

Women may experience unique mental disorders due to hormone shifts. Rates of schizophrenia and bipolar disorder are similar between genders, but onset and symptoms may differ. Women tend to use more psychotropic drugs due to limited therapeutic options. This study was aimed to estimate the prevalence of psychotropic polypharmacy among females of childbearing potential and factors impacting prescribing patterns. This was a quantitative retrospective chart review for patients admitted to inpatient units at the Mental Health Hospital in Qatar. SPSS® Statistics was used for data analysis. In addition to descriptive statistics applied, linear regression and binary logistic regression models were used to examine the clinical and sociodemographic factors associated with polypharmacy and full therapeutic response upon discharge, respectively. An alpha value of 0.05 was used. Of the 347 patients, 52.7% of the patients received a prescription of at least two psychotropic drugs upon discharge. Around two-thirds (63.1%) were prescribed at least one antipsychotic. Potential predictors of polypharmacy were age (p = 0.027), longer hospital stay (p = 0.003), family history (p < 0.001), absence of suicidal history (p = 0.005), and a diagnosis of a mood disorder (p = 0.009), or a diagnosis of a psychotic disorder (p = 0.015). A full response upon discharge was less likely to occur in patients with a longer stay (OR = 0.940; p = 0.029) and in those with a substance use disorder (OR = 0.166; p = 0.035). There is a notably high prevalence of total polypharmacy upon discharge. Some identified factors are modifiable. Evidence-based prescription practices through hospital guidelines and education should be emphasized to avoid unreasonable polypharmacy.

Morbidity and mortality risks associated with valproate withdrawal in young adults with epilepsy.

Valproate is the most effective treatment for idiopathic generalized epilepsy. Current guidance precludes its use in females of childbearing potential, unless other treatments are ineffective or not tolerated, because of high teratogenicity. This risk was recently extended to males. New guidance will limit use both in males and females aged <55 years, resulting in withdrawal of valproate from males already taking it, as occurs for females. Whether there are risks of personal harm (including injury or death) associated with valproate withdrawal has not yet been quantified for males or females ON valproate, meaning clinicians cannot reliably counsel either sex when discussing valproate withdrawal with them, despite that this concern may be at the forefront of patients' and clinicians' minds. We assessed whether there are any morbidity or mortality risks associated with valproate withdrawal in young males and females. We performed a retrospective cohort study of internationally derived electronic health data within the TriNetX Global Collaborative Network. Included were males and females aged 16-54 years with ≥1 epilepsy disease or symptom code between 1 December 2017 and 1 December 2018, and ≥2 valproate prescriptions over the preceding 2 years (1 January 2015-30 November 2017). Five-year propensity-matched risks of mortality and a range of morbidity outcomes were compared between those remaining ON versus withdrawn from valproate during the 1 December 2017-1 December 2018 recruitment period, regardless of whether switched to another antiseizure medication. Survival analysis was undertaken using Cox-proportional hazard models, generating hazard ratios (HRs) with 95% confidence intervals (CIs). In total, 8991 males and 5243 females taking valproate were recruited. Twenty-eight per cent of males and 36% of females were subsequently withdrawn from valproate. Valproate withdrawal was associated with significantly increased risks of emergency department attendance [HRs overall: 1.236 (CI 1.159-1.319), males: 1.181 (CI 1.083-1.288), females: 1.242 (CI 1.125-1.371)], hospital admission [HRs overall: 1.160 (CI 1.081-1.246), males: 1.132 (CI 1.027-1.249), females: 1.147 (CI 1.033-1.274)], falls [HRs overall: 1.179 (CI 1.041-1.336), males: 1.298 (CI 1.090-1.546)], injuries [HRs overall: 1.095 (CI 1.021-1.174), males: 1.129 (CI 1.029-1.239)], burns [HRs overall: 1.592 (CI 1.084-2.337)] and new-onset depression [HRs overall 1.323 (CI 1.119-1.565), females: 1.359 (CI 1.074-1.720)]. The risk of these outcomes occurring was 1%-7% higher in those withdrawn from valproate than in those remaining ON valproate. Overall, valproate withdrawal was not associated with increased mortality. These results may help patients and clinicians have a more informed discussion about personal safety when considering valproate withdrawal.

Survey of policies at US hospitals on the selection of RhD type of low-titer O whole blood for use in trauma resuscitation.

Low-titer group O whole blood (LTOWB) use is increasing due to data suggesting improved outcomes and safety. One barrier to use is low availability of RhD-negative LTOWB. This survey examined US hospital policies regarding the selection of RhD type of blood products in bleeding emergencies. A web-based survey of blood bank directors was conducted to determine their hospital's RhD-type selection policies for blood issued for massive bleeding. There was a 61% response rate (101/157) and of those responses, 95 were complete. Respondents indicated that 40% (38/95) use only red blood cells (RBCs) and 60% (57/95) use LTOWB. For hospitals that issue LTOWB (N = 57), 67% are supplied only with RhD-positive, 2% only with RhD-negative, and 32% with both RhD-positive and RhD-negative LTOWB. At sites using LTOWB, RhD-negative LTOWB is used exclusively or preferentially more commonly in adult females of childbearing potential (FCP) (46%) and pediatric FCP (55%) than in men (4%) and boys (24%). RhD-positive LTOWB is used exclusively or preferentially more commonly in men (94%) and boys (54%) than in adult FCP (40%) or pediatric FCP (21%). At sites using LTOWB, it is not permitted for adult FCPs at 12%, pediatric FCP at 21.4%, and boys at 17.1%. Hospitals prefer issuing RhD-negative LTOWB for females although they are often ineligible to receive RhD-negative LTOWB due to supply constraints. The risk and benefits of LTOWB compared to the rare occurrence of hemolytic disease of the fetus/newborn (HDFN) need further examination in the context of withholding a therapy for females that has the potential for improved outcomes.

Ethical considerations in the use of RhD-positive blood products in trauma.

Prehospital and early in-hospital use of low titer group O whole blood (LTOWB) for life-threatening bleeding has been independently associated with improved survival compared to component therapy. However, when RhD-positive blood products are administered to RhD-negative females of childbearing potential (FCP), there is a small future risk of hemolytic disease of the fetus and newborn (HDFN). This raises important ethical questions that must be explored in order to justify the use of RhD-positive blood products, including LTOWB, both in clinical practice and research. This essay explores the ethical challenges related to RhD-positive blood product administration to RhD-negative or RhD-unknown FCPs as a first-line resuscitation fluid in the trauma setting. These ethical issues include: issues related to decision-making, ethical analysis based on the doctrine of double effect (DDE), and attendant obligations incurred by hospitals that administer RhD-positive blood to FCPs. Ethical analysis through the use of the DDE demonstrates that utilization of RhD-positive blood products, including LTOWB, in the early resuscitation of FCPs is an ethically appropriate approach. By accepting the risk of HDFN, hospitals generate obligations to promote blood donation, evaluate for alloimmunization and counsel patients on the future risk of HDFN, and maintain an understanding of the ethical rationale for RhD-positive blood transfusion.

Maternal and child life years gained by transfusing low titer group O whole blood in trauma: A computer simulation.

Using low titer group O whole blood (LTOWB) is increasingly popular for resuscitating trauma patients. LTOWB is often RhD-positive, which might cause D-alloimmunization and hemolytic disease of the fetus and newborn (HDFN) if transfused to RhD-negative females of childbearing potential (FCP). This simulation determined the number of life years gained by the FCP and her future children if she was resuscitated with LTOWB compared with conventional component therapy (CCT). The model simulated 500,000 injured FCPs of each age between 0 and 49 years with LTOWB mortality relative reductions (MRRs) compared with components between 0.1% and 25%. For each surviving FCP, number of life years gained was calculated using her age at injury and average life expectancy for American women. The number of expected future pregnancies for FCPs that did not survive was also based on her age at injury; each future child was assigned the maximum lifespan unless they suffered perinatal mortality or serious neurological events from HDFN. The LTOWB group with an MRR 25% compared with CCT had the largest total life years gained. The point of equivalence for RhD-positive LTOWB compared to CCT, where life years lost due to severe HDFN was equivalent to life years gained due to FCP survival/future childbearing, occurred at an MRR of approximately 0.1%. In this model, RhD-positive LTOWB resulted in substantial gains in maternal and child life years compared with CCT. A >0.1% relative mortality reduction from LTOWB offset the life years lost to HDFN mortality and severe neurological events.

Not as “D”eadly as once thought – the risk of D-alloimmunization and hemolytic disease of the fetus and newborn following RhD-positive transfusion in trauma

ABSTRACTThe use of blood products to resuscitate injured and massively bleeding patients in the prehospital and early in-hospital phase of the resuscitation is increasing. Using group O red blood cells (RBC) and low titer group O whole blood (LTOWB) avoids an immediate hemolytic reaction from recipient’s naturally occurring anti-A and – B, but choosing the RhD type for these products is more nuanced and requires the balancing of product availability and survival benefit against the risk of D-alloimmunization, especially in females of childbearing potential (FCP) due to the possible future occurrence of hemolytic disease of the fetus and newborn (HDFN). Recent models have estimated the risk of fetal/neonatal death from HDFN resulting from D-alloimmunization of an FCP during her trauma resuscitation at between 0-6.5% depending on her age at the time of the transfusion and other societal factors including trauma mortality, her age when she becomes pregnant, frequency of different RHD genotypes in the population, and the probability that the woman will have children with different fathers; this is counterbalanced by an approximately 24% risk of death from hemorrhagic shock. This review will discuss the different models of HDFN outcomes following RhD-positive transfusion as well as the results of recent surveys where the public was asked about their preferences for urgent transfusion in light of the risks of fetal/neonatal adverse events.

The regional whole blood program in San Antonio, TX: A 3‐year update on prehospital and in‐hospital transfusion practices for traumatic and non‐traumatic hemorrhage

AbstractLow titer type O Rh‐D + whole blood (LTO + WB) has become a first‐line resuscitation medium for hemorrhagic shock in many centers around the World. Showing early effectiveness on the battlefield, LTO + WB is used in both the pre‐hospital and in‐hospital settings for traumatic and non‐traumatic hemorrhage resuscitation. Starting in 2018, the San Antonio Whole Blood Collaborative has worked to provide LTO + WB across Southwest Texas, initially in the form of remote damage control resuscitation followed by in‐hospital trauma resuscitation. This program has since expanded to include pediatric trauma resuscitation, obstetric hemorrhage, females of childbearing potential, and non‐traumatic hemorrhage. The objective of this manuscript is to provide a three‐year update on the successes and expansion of this system and outline resuscitation challenges in special populations.

Pregnancy Outcomes in Patients with Multiple Sclerosis Following Exposure to Ofatumumab

Background: Ofatumumab, a fully human anti-CD20 monoclonal antibody, is approved for the treatment of relapsing multiple sclerosis (RMS) in adults. As per the ofatumumab label, females of childbearing potential should use effective contraception during and for at least 6 months after discontinuation of treatment. Data on the effect of ofatumumab on pregnancy outcomes are limited in humans. Based on the current knowledge, the maternal-fetal transfer of IgG during the first trimester is minimal and fetal IgG concentration starts to rise from the second trimester.

The risk to future pregnancies of transfusing Rh(D)-negative females of childbearing potential with Rh(D)-positive red blood cells during trauma resuscitation is dependent on their age at transfusion.

A risk assessment model for predicting the risk of haemolytic disease of the fetus and newborn (HDFN) in future pregnancies following the transfusion of Rh(D)-positive red blood cell (RBC)-containing products to females of childbearing potential (FCP) was developed, accounting for the age that the FCP is transfused in various countries. The HDFN risk prediction model included the following inputs: risk of FCP death in trauma, Rh(D) alloimmunization rate following Rh(D)-positive RBC transfusion, expected number of live births following resuscitation, probability of carrying an Rh(D)-positive fetus, the probability of HDFN in an Rh(D)-positive fetus carried by an alloimmunized mother. The model was implemented in Microsoft R Open, and one million FCPs of each age between 18 and 49years old were simulated. Published data from eight countries, including the United States, were utilized to generate country-specific HDFN risk estimates. The risk predictions showed similar characteristics for each country in that the overall risk of having a pregnancy affected by HDFN was higher if the FCP was younger when she received her Rh(D)-positive transfusion than if she was older. In the United States, the overall risk of HDFN if the FCP was transfused at age 18 was 3·4% (mild: 1·20%, moderate: 0·45%; severe: 1·15%; IUFD: 0·57%); the risk was approximately 0% if the FCP was 43years or older at the time of transfusion. This model can be used to predict HDFN outcomes when establishing transfusion policies as it relates to the administration of Rh(D)-positive products for massively bleeding FCPs.

Perimenstrual Asthma in Aspirin-Exacerbated Respiratory Disease

Aspirin-exacerbated respiratory disease (AERD) is a condition of the upper and lower respiratory tract characterized by reactions to nonsteroidal anti-inflammatory drugs. The Severe Asthma Research Program reported a strong association between perimenstrual asthma (PMA) and aspirin-sensitive asthma. To evaluate the prevalence and characteristics of PMA among a cohort of patients with AERD. Women 18 years and older enrolled in the Brigham and Women's AERD registry were surveyed about their reproductive, asthma, and sinus history. Subjects reporting the development of asthma before menopause were included. Continuous and categorical variables were compared between those reporting menstruation as a trigger for asthma symptoms and those who did not. Covariates expected a priori to have a positive effect on the odds of PMA were included in a multivariate logistic regression model to test associations between PMA and clinical factors. Among females of childbearing potential, 369 of 695 responded to the survey and 322 met inclusion criteria. Twenty-four percent of subjects (n= 74) reported PMA. Earlier age of AERD onset, concurrent worsening of sinus symptoms the week before or during menstruation, increased emergency department visits for asthma, and a change in the severity of respiratory symptoms at menopause were more common in PMA. Earlier age at first nonsteroidal anti-inflammatory drug-induced respiratory reaction and emergency department visits increased the odds of reporting PMA. PMA and increased sinus symptoms with menstruation are common in females with AERD. Females with AERD should be counseled about upper and lower respiratory symptom deterioration with menstruation.

Inappropriate sinus tachycardia – symptom and heart rate reduction with ivabradine: pooled analysis of prospective studies

Objective: Inappropriate sinus tachycardia (IST), is a debilitating condition despite currently available treatment. Ivabradine, a selective sinus node blocker, has been used off-label to treat IST. We therefore systematically reviewed the literature and analyzed the quality of existing data and calculated sample size estimates for adequately powered studies. Methods: We included all available trials, open label prospective studies studies with ivabradine, specifically for IST among subjects with no structural heart disease with a minimum follow-up period of > 2 weeks. Heart rate and symptom reduction with ivabradine were estimated based on results of subjective change in symptoms assessed by data instruments used in the studies. All studies were assessed for quality using two validated checklists scoring the quality of studies. Sample size estimates for future studies were calculated based on the magnitude of symptom reduction encountered after treatment with ivabradine. Results: Nine studies met study criteria, culminating in 145 patients pooled with the majority being women (> 70%). All studies were small, most inadequately powered. All studies reported a decrease in maximum and/or mean resting heart rate with ivabradine. Symptom reduction demonstrated either complete or considerable amelioration. Most studies were at least of moderate quality. Excellent consistency of study quality was gauged by both data-quality tools and narrow limits of agreement between these tools. Calculated sample size estimates for adequately powered studies with a placebo effects of 30 and 50% was 56 and 242 patients respectively. Conclusions: Although ivabradine is effective in reducing heart rate and symptoms in IST patients, none of the studies were adequately powered to account for the expected placebo effect on symptoms. A multicenter-randomized, placebo controlled active comparative study with a beta-blocker is needed to confirm these findings. This is relevant given the ivabradine’s potential teratogenic effect as many IST patients are females of childbearing potential.

Inappropriate sinus tachycardia–symptom and heart rate reduction with ivabradine: A pooled analysis of prospective studies

Inappropriate sinus tachycardia (IST) is debilitating despite available treatment. Off-label use of ivabradine for IST prompted this systematic analysis of existing data quality and sample size estimates for adequately powered studies. To determine clinical efficacy of ivabradine in IST from pooled prospective studies. Analysis included ivabradine studies for IST participants without structural heart disease and with follow-up of ≥2 weeks. Heart rate and symptom reduction with ivabradine were estimated based on results of subjective change in symptoms assessed by various data instruments used in each study. Studies were assessed for quality using validated checklists. Sample sizes were calculated based on the magnitude of symptom reduction encountered after treatment with ivabradine. Nine studies met criteria, culminating in 145 patients pooled. Most patients were women (≥70%). Studies were small and not adequately powered, and all reported a decrease in maximum or mean resting heart rate or both, with complete or considerable amelioration of symptoms with ivabradine. Most studies had moderate quality with excellent consistency of study quality and narrow limits of agreement between the quality checklists. Sample size estimates for adequately powered studies with various placebo effects and comparisons with β-blockade are reported. Ivabradine effectively reduces heart rate and symptoms in IST, but no study was adequately powered to account for the expected placebo effect on symptoms. A multicenter, randomized, placebo-controlled, active, comparative study with a β-blocker is needed for confirmation. This is especially relevant given the ivabradine's potential teratogenic effect, as many IST patients are females of childbearing potential.

Strategies to identify candidates for D variant genotyping.

RhD variants have altered D epitopes and/or decreased antigen copies per red cell. Individuals carrying these variants may test antigen negative, weakly positive, or positive by serology, and may or may not be at risk of alloimmunisation after exposure. There have been recommendations to perform RHD genotyping of patients, pregnant women and females of childbearing potential with serological weak D phenotype, to guide prophylactic use of Rh immune globulin (RhIG), and better conserve D-negative blood products. The purpose of this study was to evaluate the performance of a set of empirical criteria to identify such patients. A two-method strategy of gel testing (GT) and tube testing (TT) was used for Rh typing of patients with no historical blood type in the present institution. A monoclonal-polyclonal blend anti-D was used for Rh typing by TT at immediate spin. Three empirical criteria were used to identify candidates for genotyping: C1: discrepancy between the two test methods and a GT reaction strength >2+ stronger than TT; C2: weak serological reaction, defined as reaction strength ≤2+ regardless of testing method if both GT and TT were performed or reaction strength ≤2+ if only GT was performed, or reaction strength ≤1+ if only TT was performed; C3: presence of anti-D in D-positive patients with no history of RhIG use in the preceding 3 months and in whom alloanti-D is suspected. Overall, 50 patients, ranging from newly born to 93 years old, were identified. Genomic testing confirmed D variants in 49/50 cases with a positive predictive value of 98%. This two-method strategy is a powerful screening tool for identifying candidates for RHD genotyping. This strategy meets the current requirements of two blood type determinations/two specimens in pre-transfusion testing while simultaneously identifying candidates for RHD genotyping with a minimal increase in work load and cost.

Risk Management of Teratogenic Drugs ~The Current States of Practice in Europe, US and Japan~

Thalidomide was approved for the treatment of multiple myeloma in Japan under a risk management program, named TERMS, in 2008. Since then, we have been conducting a survey of the stakeholders to assess the effectiveness of TERMS. These surveys showed patients had enough knowledge of the risks of thalidomide. In the USA, legislation in 2007 granted its U.S. Food and Drug Administration (FDA) the authority to require Risk Evaluation and Mitigation Strategies (REMS) when necessary to ensure that a drug's benefits outweigh its risks. As of 2015, more than 70 drugs, including thalidomide, have REMS programs. In Germany, in the early 1960s, over 5000 children were born with deformities. Therefore, the safety regulations in Germany go far beyond the European Medicines Agency (EMA) safety regulations at the time of thalidomide re-approval; thalidomide can be prescribed by a special prescribing form, including both proof of the patients' awareness of information about the risks, and participation in a pregnancy prevention program. While Japan has taken similar safety measures, a portion of thalidomide is still privately imported there. By March 2013, 594 patients have been registered to Japan's Safety Management System for Unapproved Drugs (SMUD), which was introduced by the Ministry of Health, Labour and Welfare (MHLW) in 2009. The number of females of child bearing potential (FCBPs) was 33 and the fraction (33/594=5.6%) was higher than that (48/7370=0.7%) in the case of TERMS. Risk management of thalidomide is described in this review.

It's time to phase in RHD genotyping for patients with a serologic weak D phenotype. College of American Pathologists Transfusion Medicine Resource Committee Work Group.

It's time to phase in RHD genotyping for patients with a serologic weak D phenotype. College of American Pathologists Transfusion Medicine Resource Committee Work Group.

Translational pharmacokinetic modelling and simulation for the assessment of duration of contraceptive use after treatment with miltefosine

Use of miltefosine in the treatment of visceral leishmaniasis (VL) is hampered by its potential teratogenicity. The duration of adequate contraceptive cover in females of child-bearing potential after cessation of a potentially teratogenic drug therapy remains debated. The objective of this study was to provide a rational approach to suggest durations of contraceptive cover for various miltefosine regimens. A human reproductive safety threshold exposure limit was derived using animal-to-human dose conversion. Pharmacokinetic (PK) data for miltefosine in females are lacking; a previously developed population PK model and a comprehensive anthropometric dataset were used to simulate PK data for Indian female VL patients receiving miltefosine for 5, 7, 10 or 28 days. Probability of supra-threshold miltefosine exposure was used to evaluate adequate durations of post-treatment contraceptive cover for the various regimens. PK data were simulated for 465 treated Indian female VL patients of child-bearing potential with a median age of 25 years (IQR 16-31 years) and median weight of 38 kg (IQR 34-42 kg). From animal reproductive toxicity studies, a human reproductive safety threshold exposure limit was derived of 24.5 μg · day/mL. Probability of 'unprotected' supra-threshold miltefosine exposure was very low (<0.2%) for a post-treatment contraceptive cover period of 4 months for the standard 28 day regimen, and of 2 months for the shorter regimens. To our knowledge, this is the first study providing rational suggestions for contraceptive cover for a teratogenic drug based on animal-to-human dose conversion. For the 28 day miltefosine regimen, post-treatment contraceptive cover may be extended to 4 months, whereas for all shorter regimens 2 months may be adequate.

Practical approaches to the use of lenalidomide in multiple myeloma: a canadian consensus.

In Canada, lenalidomide combined with dexamethasone (Len/Dex) is approved for use in relapsed or refractory multiple myeloma (RRMM). Our expert panel sought to provide an up-to-date practical guide on the use of lenalidomide in the managing RRMM within the Canadian clinical setting, including management of common adverse events (AEs). The panel concluded that safe, effective administration of Len/Dex treatment involves the following steps: (1) lenalidomide dose adjustment based on creatinine clearance and the extent of neutropenia or thrombocytopenia, (2) dexamethasone administered at 20–40 mg/week, and (3) continuation of treatment until disease progression or until toxicity persists despite dose reduction. Based on available evidence, the following precautions should reduce the risk of common Len/Dex AEs: (1) all patients treated with Len/Dex should receive thromboprophylaxis, (2) erythropoiesis-stimulating agents (ESAs) should be used cautiously, and (3) females of child-bearing potential and males in contact with such females must use multiple contraception methods. Finally, while Len/Dex can be administered irrespective of prior therapy and in all prognostic subsets, patients with chromosomal deletion 17(p13) have less favorable outcomes with all treatments, including Len/Dex. New directions for the use of lenalidomide in RRMM are also considered.

Phase I Study of the Combination of 5-Azacitidine Sequentially with High-Dose Lenalidomide in Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia (AML)

Abstract 2613The hypomethylating agents are standard of care in patients with higher risk MDS and used frequently in older AML. A number of strategies, including combination approaches, are being developed to improve results of single agent hypomethylating agent. For instance the combination of 5-azacitidine and lenalidomide (LEN) has been shown to be safe and active in a phase I trial (Sekeres JCO 2010; 28:2253–8). Recently the use of high dose LEN (50 mg orally daily) has been reported to have significant activity in older AML (Vij Blood. 2011;117:1828–33). We hypothesized that sequential combination of 5-azacitidine followed by LEN could be safe and active in patients with higher risk MDS and AML. To test this concept, we developed a phase I/II protocol of such combination. Here, we present results from the completed phase I portion of the study. Patients with refractory or relapsed AML and MDS (bone marrow blasts more than 10%) of any age or untreated patients older than 60 years with AML or MDS who refused or were not eligible for frontline therapy were eligible. Adequate performance status, liver function and renal function were requiered. All study participants were registered into RevAssist® program. Females of childbearing potential were required to have a negative pregnancy test. 5-azacitidine was administered at 75 mg/m2 IV daily for 1 to 5 day on a 28 day cycle. LEN was administered on day 6 for 5 or 10 days. The phase I portion of the study design followed a classic “3+3” design and only LEN was dose escalated. 28 patients were registered in the study. The following doses of LEN were used: 10 (N=5), 15 (N=3), 20 (N=3), 25 (N=3), 50 (N=4), 75 mg (N=3) orally for 5 days and 75 for 10 days (N=7). Median age was 65 (range 31 to 79); 19 patients had AML and 9 had MDS or CMML. Median baseline WBC was 1.95 K/μL (range 0.1 to 19.1), median platelet count 68 K/μL (4 to 328), median bone marrow blasts 23% (range 11% to 84%), 8 had diploid cytogenetics and 20 others including 5q- (8 patients), monosomy 5 (5 patients) and monosomy 7(7 patients), del 17 (4 patients), t(9:11)(2 patients) and t(3;5)(2 patients). FLT-3 and N-RAS mutations were seen in 2 patients each and NPM-1 mutation in 1 patient. 22 patients had received prior therapy. A total of 88 cycles of therapy have been administered with a median of 1.5 cycles (range 1 to 10). No dose limiting toxicity was documented and the maximal tolerated dose was therefore not reached. At the 75 mg × 10 days dose, one patient died unexpectedly and subsequently 6 additional patients were treated with no additional severe toxicities observed. Common non-hematological toxicities were fatigue, loss of appetite, constipation, skin rash, fevers and weight loss. Of 6 patients that had not received prior therapy, 5 were evaluable for response and 3 (60%) achieved a complete response at doses of 25 and 50 mg of LEN. No response was observed in previously treated patients but 9 (47%) had stable disease. In conclusion, the combination of 5-azacitidine with high dose LEN up to 75 mg orally × 10 days is safe in patients with AML/MDS. The study continues now in a phase II extension of N=40 patients with LEN at a dose of 50 mg daily × 10 days. Disclosures:No relevant conflicts of interest to declare.

Dermatologists’ level of compliance with the prescription guidelines of isotretinoin for females of childbearing potential

Potent teratogenicity limits the use of isotretinoin among females of childbearing potential (FCBP). To explore the current practice of dermatologists for pregnancy prevention when prescribing isotretinoin for FCBP. A self-administered questionnaire was distributed to 160 dermatologists attending a national conference in Riyadh, Saudi Arabia, in 2008. The survey was designed to capture the details of precautions taken by dermatologists to prevent pregnancy among isotretinoin users. Ultimately, 134 dermatologists completed the questionnaire (84% response rate). Their mean age was 39 ± 9.5 years. A total of 82 were female (65%). The median number of FCBP for whom isotretinoin was prescribed by each dermatologist during the previous 12 months was two (range from 0 to 30). Of the 792 total FCBP, seven were reported to have become pregnant (incidence rate of 8.8/1000) while on isotretinoin. Out of those seven, three women terminated the pregnancy (elective abortions: 42.7%). The majority of the dermatologists (79%) always obtained written consent and discussed teratogenic risks (98%); 44% provided written information about potential isotretinoin teratogenicity, and 30% offered printed information on contraception. Survey results also revealed that 62% recommended double contraception for FCBP, 60% always recommended pregnancy testing prior to therapy, but only 16% requested monthly pregnancy tests. In general, 62.4% avoided isotretinoin prescription to FCBP, which was independent of dermatologists' gender, years of experience, or having a previous incident of isotretinoin-exposed pregnancy. Some dermatologists still do not follow the recommendations for isotretinoin prescription to FCBP. This needs to be corrected, especially in countries with restrictions on abortion.

Benefit-Risk Assessment of Leflunomide

Evidence is accumulating for the early sustained usage of disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis. Leflunomide was licensed for the treatment of rheumatoid arthritis in 1998. Postmarketing surveillance, case reports and observational studies have highlighted less common or unexpected adverse events. Therefore, it is appropriate that we review the benefit-risk profile of leflunomide after 10 years of widespread usage. A wide-based search of relevant literature was performed to formulate this assessment. The improvements in rheumatoid arthritis shown by double-blind, randomized controlled trials (RCTs) of leflunomide have now been shown to be maintained beyond 4 years in open-label extension studies. Leflunomide is comparable to methotrexate, but better than sulfasalazine at 24 months in only one study. However, tolerance in clinical practice research shows higher than expected withdrawal rates due to both toxicity and lack of efficacy when compared with methotrexate and placebo. Adverse events reported include gastrointestinal upset, hypertension, headache, hepatotoxicity and hair loss, as well as predisposition to infection and peripheral neuropathy. The incidence of gastrointestinal adverse effects for leflunomide is similar to sulfasalazine but higher than those seen with methotrexate. Serious drug-induced hepatotoxicity leading to hospitalization is rare (0.02%), but isolated fatalities from liver failure have been documented. It is considered likely, but not yet proven, that there may be an increased incidence of weight loss and interstitial lung disease with leflunomide. Leflunomide in combination with methotrexate or sulfasalazine is an effective regimen in RCTs utilizing placebo controls, but more research is needed to confirm its effectiveness in combination with other DMARDs, particularly biologicals. The active metabolite of leflunomide is teratogenic in animal studies and is also found in breast milk. Therefore, contraception is advised in both males and females of child-bearing potential. There are genetic, pharmacokinetic and biochemical reasons to explain variation in both patient response and adverse event profile. Hence, blood and blood pressure monitoring are recommended and therapeutic drug monitoring should be considered in clinical nonresponders. Leflunomide is an effective DMARD that sustains a clinical and radiological response comparable to sulfasalazine and methotrexate. However, adverse effects necessitate frequent monitoring. It should be used with caution in those of child-bearing potential and with pre-existing lung and liver disease.